Excess exposure to manganese (Mn) due to occupational settings can cause damage to the nervous system. Symptoms of Mn intoxication ("manganism") resemble those in idiopathic Parkinson's disease (IPD) and usually become progressive and irreversible, making early diagnosis crucial for prevention of Mn intoxication in the occupational and environmental setting. Therefore the primary objective of the proposed work is to use novel neuroimaging techniques to discover and establish a noninvasive diagnostic tool for early detection of Mn-induced Parkinsonism in humans, and to further explore the underlying mechanism of Mn neurotoxicity in an animal model. Studies on rodents and humans have linked increased Mn exposure with alterations in the content of the neurotransmitter 3-aminobutyric acid (GABA) in the basal ganglia brain region, similar to those found in movement disorders. However the dose-dependency, specificity and the mechanism underlying these alterations is unknown. Novel approaches in magnetic resonance spectroscopy (MRS) will be used to detect in vivo concentration changes of brain GABA as well as N- acetylaspartate (NAA), a marker of neuronal integrity, and [11C]CFT PET will be used to assess dopamine (DA) neurodegeneration. The following three hypotheses will be tested: (1) pre-symptomatic onset of manganism can be detected by increased GABA and decreased NAA levels in selected brain regions in combination with brain Mn and Fe levels, (2) Mn-induced changes of striatal GABA levels are independent of degeneration of striatal DA neurons and (3) Mn-induced GABA and NAA changes are detectable in multiple brain areas. To establish a unique relationship between GABA/NAA changes, cumulative Mn exposure, internal exposure parameters (such as brain, blood and urine Mn levels), and Mn-induced motor deficits, a longitudinal study (two time points over 4 years) will be established on a well-established cohort of Mn-exposed subjects in China (24 workers with low and with high Mn exposure each, 24 control subjects and 15 manganism patients). A group of 24 IPD patients will be used as positive controls for GABA changes in movement disorders. To define the difference between Mn-induced parkinsonism and IPD, we will explore the mechanistic relationship between GABA and dopamine in two levels of Mn-exposure and a drug-induced (6-OHDA) PD rodent model by consecutive MRS and PET imaging in the same animals (N=10 per group) in Aim 2. Finally, we will investigate the spatial distribution of GABA and NAA changes due to low-level chronic Mn exposure in a local Indiana welder cohort (N=30, 15 controls) by using our fast 3D spectroscopic imaging (MRSI) technique currently under development on our local scanner. The knowledge to be gained from this work will lead to new insights about the mechanism and dose-effect of Mn-induced neurotoxicity and potentially result in a diagnostic tool allowing for early, pre-symptomatic diagnosis of Mn induced Parkinsonism. PUBLIC HEALTH RELEVANCE: Excessive occupational exposure to manganese in the alloying and steel industry is known to cause Parkinson-like symptoms, which progress even after the cessation of the exposure. Neither a biomarker for early, pre-symptomatic diagnosis, nor effective treatment options exist to date. Using novel, non-invasive neuroimaging techniques such as magnetic resonance spectroscopy and positron-emission tomography to measure the changes in brain neurotransmitter levels altered by manganese exposure, and studying the dose-effect relationship of such changes, will provide critical insight to the mechanism of manganese- induced neurotoxicity and will benefit early clinical diagnosis.